Induction of tolerance is an effective strategy to prevent transplantation rejection and autoimmunity. Apoptotic deletion of T cells is a major mechanism utilized by both the central (thymus) and peripheral immune system to establish tolerance to self-antigens. Therefore, understanding the mechanisms regulating T cell apoptosis is critical for the development of therapeutic strategies for tolerance induction. PKC-? (protein kinase C) selectively mediates T cell receptor (TCR) signals that control T cell survival and activation. Highly specific PKC- ? inhibitors are thus believed to be able to prevent T cell-dependent allograft rejection. The objective of this application is to study PKC-? function using a highly reliable cardiac allograft rejection model, and to develop PKC-?-based therapeutic allograft rejection prevention strategies. Based on the knowledge learned from the studies, we expect to develop PKC-?-based comprehensive treatments for prevention of allograft rejection. It is also expected that such treatments will have a broader applicability in the prevention of T cell-mediated autoimmunity, such as rheumatoid arthritis and systematic lupus erythematosus. In addition, the research has significance to basic T cell biology, as it is expected to reveal novel molecular mechanisms responsible for PKC-?-regulated T cell apoptosis and PKC-8 compensatory mechanisms. PUBLIC HEALTH RELEVANCE: This proposal is to study the mechanisms responsible for PKC-?-regulated immune responses in vivo using an acute cardiac allograft rejection model.